Three new kenpaullone derivatives with a modified parent ring system (III), (X) and (XI) are synthesized in order to develop kinase inhibitors with enhanced selectivity. Among them, 1-azakenpaullone (X) is found to act as a selective GSK-3β versus CDK1 inhibitor. -(KUNICK*, C.; LAUENROTH, K.; LEOST, M.; MEIJER, L.; LEMCKE, T.; Bioorg. Med. Chem. Lett. 14 (2004) 2, 413-416; Inst. Pharm. Chem., TU Braunschweig, D-38106 Braunschweig, Germany; Eng.) -Staver 18-172

We describe a refined homology model of a CDK1/cyclin B complex that was previously used for the structure-based optimization of the Paullone class of inhibitors. The preliminary model was formed from the homologous regions of the deposited CDK2/cyclin A crystal structure. Further refinement of the CDK1/cyclin B complex was accomplished using molecular mechanics and hydropathic analysis with a protocol of constraints and local geometry searches. For the most part, our CKD1/cyclin B homology model is very similar to the high resolution CDK2/cyclin A crystal structure regarding secondary and tertiary features. However, minor discrepancies between the two kinase structures suggest the possibility that ligand design may be specifically tuned for either CDK1 or CDK2. Our examination of the CDK1/cyclin B model includes a comparison with the CDK2/cyclin A crystal structure in the PSTAIRE interface region, connecting portions to the ATP binding domain, as well as the ATP binding site itself.

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Epoxide moieties are incorporated into the scaffold of kenpaullone and 9-trifluoromethylpaullone by Stille coupling to introduce the unsaturated side chains, followed by epoxidation of the C,C-double bonds using a peroxide/nitrile mixture. The growth-inhibitory properties of paullones (IV), (VI), (IX) and (XV) are compared with the results for kenpaullone. All novel derivatives reveal a stronger general antiproliferative activity. -(XIE, X.; LEMCKE, T.; GUSSIO, R.; ZAHAREVITZ, D. W.; LEOST, M.; MEIJER, L.; KUNICK*, C.; Eur. J. Med. Chem. 40 (2005) 7, 655-661; Inst. Pharm.